Given our previous evidence that MΦ-derived HMGB1 participates in paclitaxel-induced peripheral neuropathy, we studied possible role of HMGB1 in the neuropathy caused by bortezomib (BTZ), a proteasome inhibitor used for treatment of multiple myeloma. To create BTZ-induced peripheral neuropathy (BIPN) in mice, BTZ was administered i.p. 3 times weekly for 2 weeks. The development of BIPN was prevented by an anti-HMGB1-neutralizing antibody (Ab) and antagonists of RAGE or CXCR4, but not Toll-like receptor 4, among targets for HMGB1, and by minocycline, an inhibitor of MΦ/microglia, ethyl pyruvate, known to inhibit HMGB1 release from MΦ, or liposomal clodronate, a MΦ depletor. Only Ab, the RAGE antagonist or minocycline, when given once on day 14, reversed the sustained BIPN. In the dorsal root ganglion, MΦ accumulation was detected on day 3, but not 14, of BTZ treatment, and RAGE upregulation was found on day 14. BTZ directly caused HMGB1 release from MΦ-like RAW264.7 cells. Our data suggest the involvement of RAGE and CXCR4 activation by MΦ-derived HMGB1 in the development of BIPN, and of RAGE activation by HMGB1 released from non-MΦ cells in the sustained period of BIPN.